The release of a hormone (a biochemical substance that is produced by a specific cell or tissue and causes a change or an activity in a cell or tissue located elsewhere in the organism) by the anterior lobe of the pituitary gland (which is located at the base of the brain and secretes hormones related to growth and sexual development) usually requires the prior release of another class of hormones produced by the hypothalamus (a structure in the lower part of the brain that is connected to and controls the pituitary gland). One of the hypothalamic hormones acts as a factor that triggers the release of the gonadotropic hormones, particularly LH (luteinizing hormone, which is the pituitary hormone that causes the testicles in men and ovaries in women to manufacture sex hormones) and FSH (follicle-stimulating hormone, which is the pituitary hormone that stimulates follicle growth in women and sperm formation in men). This hormone is referred to herein as "GnRH" (gonadotropin-releasing hormone) and/or "LH-RH" (luteinizing hormone-releasing hormone). GnRH is a decapeptide hormone produced by the arcuate nuclei of the hypothalamus (an arcuate nucleus is any of the cellular masses in the thalamus, hypothalamus, or medulla oblongata) that controls the pituitary gland's production and release of gonadotropins (hormones including FSH and LH that are produced by the pituitary gland that control reproductive function). GnRH (LH-RH) may be represented by the sequence pyro-Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH.sub.2 or, in the single-letter code designation, pyro-EHWSYGLRPG-NH.sub.2. GnRH acts on high-affinity pituitary receptors to stimulate LH and FSH production and release.
The pituitary response to GnRH varies greatly throughout life. GnRH and the gonadotropins first appear in the fetus at about ten weeks of gestation. The sensitivity to GnRH declines, after a brief rise during the first three months after birth, until the onset of puberty. Before puberty, the FSH response to GnRH is greater than that of LH. Once puberty begins, sensitivity to GnRH increases, and pulsatile LH secretion ensues. Later in puberty and throughout the reproductive years, pulsations occur throughout the day, with LH responsiveness being greater than that of FSH. After menopause, FSH and LH concentrations rise, and postmenopausal FSH levels are higher than those of LH.
Pulsatile GnRH release results in pulsatile LH and FSH release. However, sustained infusion of GnRH and its analogs results in inhibition of LH and FSH release. This phenomenon has been utilized in the successful treatment of gonadotropin-mediated precocious puberty by the sustained administration of LH-RH or its analogs. Conversely, in people with GnRH deficiency, the pulsatile administration of LH-RH can restore a normal menstrual cycle or normal sperm and testosterone production.
GnRH agonists, which are compounds that stimulate the pituitary gland to release or modulate FSH and LH, have been the mode of choice for treating sex-steroid-dependent pathophysiologies, owing to the limited number of suitable antagonists available for clinical evaluation. GnRH antagonists, which are compounds that suppress the pituitary gland from releasing FSH and LH, however, are now being considered.
GnRH antagonists may be useful for suppressing gonadotropin secretions and preventing ovulation in female mammals. GnRH antagonists have been investigated for contraception and for regulating conception periods, as well as for treating infertility, for controlling induction of ovulation in women with chronic anovulation, and for in vitro fertilization. GnRH antagonists may also be useful for the treatment of precocious puberty, endometriosis (including endometriosis with pain), acne, amenorrhea (e.g., secondary amenorrhea), uterine myoma, ovarian and mammary cystic diseases (including polycystic ovarian disease), and breast and gynecological cancers. GnRH antagonists may also be useful in the symptomatic relief of premenstrual syndrome (PMS). They may also be used to treat ovarian hyperandrogenism and hirsutism. Antagonists have also been found useful to regulate the secretion of gonadotropins in male mammals and may be employed to arrest spennatogenesis, e.g., as male contraceptives for treatment of male sex offenders, and for treatment of prostatic hypertrophy. More specifically, GnRH antagonists may be used to treat steroid-dependent tumors, such as prostatic and mammary tumors, and for the control of the timing of ovulation for in vitro fertilization. GnRH antagonists may also be used to treat patients having illnesses, such as AIDS, wherein stimulation of the thymus to produce T-cells would be beneficial. All such uses relate to the ability of the GnRH antagonist to block the activity of GnRH.
Heretofore, available GnRH antagonists have primarily been peptide analogs of GnRH. See, e.g., International Publication No. WO 93/03058. Peptide antagonists of peptide hormones are often quite potent; however, the use of peptide antagonists is typically associated with problems because peptides are degraded by physiological enzymes and often poorly distributed within the organism being treated. Thus, they have limited effectiveness as drugs. Consequently, there presently exists a need for non-peptide antagonists of the peptide hormone GnRH.